The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences--e.g., gastrointestinal irritation and the like--are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration.
Relatively recent advances in transdermal drug delivery have enabled effective administration of a variety of drugs through the skin. These advances include the development of a number of skin penetration enhancing agents, or "permeation enhancers," to increase skin permeability, as well as non-chemical modes for facilitating transdermal delivery, e.g., the use of iontophoresis, electroporation or ultrasound. Nevertheless, the number of drugs that can be safely and effectively administered through the skin, without concomitant problems such as irritation or sensitization, remains limited.
The present invention is directed to novel drug delivery systems which have "supersaturated" drug reservoirs, and are thus able to deliver greater quantities of drug, at higher fluxes, than possible with prior transdermal systems. The novel delivery systems, by virtue of their supersaturated drug reservoirs, also reduce or in some cases eliminate the need for skin permeation enhancers. Further, smaller transdermal patches may be made using the inventive technology, i.e., patches that are at least as effective as prior patches in terms of overall drug release and drug flux, but are significantly reduced in terms of size.
None of the art of which applicants are aware describes transdermal drug delivery system having supersaturated drug reservoirs or methods for manufacturing such systems as disclosed and claimed herein. However, the following references are of interest:
U.S. Pat. No. 4,409,206 to Stricker relates to a method for preparing transdermal drug delivery systems containing the active substance in an amorphous form. Initially, a polyacrylate film is prepared by solvent casting. A drug solution or suspension is then applied to the film and the solvent is removed by evaporation. There is no disclosure concerning a heating step to dissolve the drug.
U.S. Pat. No. 4,746,509 to Haggiage et al. describes transdermal medicaments with the active ingredient dispersed in a drug reservoir in crystalline and/or solubilized form.
U.S. Pat. No. 4,832,953 to Campbell et al. describes a method for making drug delivery systems containing liquid drugs capable of forming crystalline hydrates. The drug delivery systems are heated above the melting temperature of the pure drug, after preparation of the systems, to prevent crystalline hydrate formation.
U.S. Pat. No. 4,883,669 to Chien et al. describes a transdermal drug delivery system for the administration of estradiol, wherein drug is microdispersed in a polymeric matrix disc layer which serves as the drug reservoir. The reservoir components are heated to a relatively low temperature, below the melting point of estradiol, during device manufacture.
U.S. Pat. No. 5,332,576 to Mantelle describes preparation of compositions for topical application, wherein drug is added to certain components, not including the bioadhesive carrier, and then heated at a temperature in the range of about 70.degree. C. to 90.degree. C. until all of the drug is dissolved. After the solution is cooled, the bioadhesive is added and the composition is applied to a backing material.
PCT Publication No. WO94/10984, inventors Horstmann et al., describes transdermal systems for the administration of estradiol, having drug concentrations in between the solubility of drug in the system when exposed to moisture and the solubility of the drug in the dry system. The system does not appear to be "supersaturated," if at all, until exposure to moisture. This is in contrast to the systems which may be prepared using the method of invention, which are supersaturated in the dry state. Hence, one would expect that systems from our invention would produce higher fluxes than those in this PCT publication.
Davis et al., "Effect of Supersaturation on Membrane Transport on Membrane Transport: 1. Hydrocortisone Acetate," International Journal of Pharmaceutics 76:1-8 (1991) and Pellet et al. "Effect of Supersaturation on Membrane Transport: 2. Piroxicam," International Journal of Pharmaceutics 111:1-6 (1994), present studies evaluating drug flux from supersaturated solutions of drug in propylene glycol/water formulations. Drug is first dissolved in solvent and then a supersaturated solution is made by added a second solvent thereto; no heating step is involved.